The proposed investigator-initiated project is a revision of a previous application that received an encouraging initial review. The application focuses on P-glycoprotein (P-gp) as an important modulator of brain access and, therefore, pharmacologic effects of antipsychotic drugs. Antipsychotic drugs (APD) are the primary pharmacological intervention in the treatment of severe mental illness with psychotic symptoms. The proposed animal studies are designed to produce data that may contribute to improving the outcome of pharmacotherapy with APD. While the pathways of elimination of the APD have been defined, only sparse data exist on the role of drug transporters in their disposition and effects. The most widely studied gene of the ABC cassette family of transporters, ABCB1 (also known as MDR1), is highly polymorphic and encodes for P-gp. P-gp plays a protective role for major organs by effluxing its substrates into the intestinal lumen, bile, urine, and by limiting their passage across the placenta and accumulation in the central nervous system. We will test the hypothesis that P-gp is an important modulator of brain access and pharmacologic effects of a subclass of APD, the atypicals. Similarly, we will test whether inhibition and induction of P-gp in the endothelial cells at the blood brain barrier increases or decreases, respectively, the brain exposure to, and effects of, APD. The specific aims are: (i) to evaluate the atypical APD as substrates of P-gp using transgenic mice; (ii) to determine the effects of P-gp inhibition and induction on plasma and tissue concentrations of APD; (iii) to assess neurotransmitter changes in the brain of P-gp inhibited animals using extracellular microdialysis of dopamine; and (iv) to measure behavioral changes in rats accompanying P-gp inhibition that are predictive of antipsychotic efficacy. This novel data may potentially guide future human trials to improve APD efficacy and/or tolerability with use of adjunctive P-gp modulators. The results of this research will provide support for translational studies in humans to refine treatment guidelines for the use of this class of medications in severely mentally ill patients.